Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, USA.
Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, USA.
Nat Metab. 2023 Jan;5(1):41-60. doi: 10.1038/s42255-022-00711-9. Epub 2023 Jan 19.
Oxidative stress modulates carcinogenesis in the liver; however, direct evidence for metabolic control of oxidative stress during pathogenesis, particularly, of progression from cirrhosis to hepatocellular carcinoma (HCC), has been lacking. Deficiency of transaldolase (TAL), a rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway (PPP), restricts growth and predisposes to cirrhosis and HCC in mice and humans. Here, we show that mitochondrial oxidative stress and progression from cirrhosis to HCC and acetaminophen-induced liver necrosis are critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Both TAL and AR are confined to the cytosol; however, their inactivation distorts mitochondrial redox homeostasis in opposite directions. The results suggest that AR acts as a rheostat of carbon recycling and NADPH output of the PPP with broad implications for disease progression from cirrhosis to HCC.
氧化应激调节肝脏的癌变；然而，在发病机制中，特别是在从肝硬化到肝细胞癌（HCC）的进展过程中，代谢控制氧化应激的直接证据一直缺乏。转醛醇酶（TAL）是戊糖磷酸途径（PPP）非氧化分支的限速酶，其缺乏会限制生长，并导致人和小鼠发生肝硬化和 HCC。在这里，我们表明，线粒体氧化应激以及从肝硬化到 HCC 的进展和对乙酰氨基酚引起的肝坏死，严重依赖于醛糖还原酶（AR）的 NADPH 耗竭和多元醇的积累，而这种酶可以防止 PPP 中的碳捕获和 TAL 缺乏引起的生长受限。TAL 和 AR 都局限于细胞质；然而，它们的失活以相反的方向扭曲了线粒体氧化还原稳态。结果表明，AR 作为 PPP 的碳回收和 NADPH 输出的变阻器发挥作用，对从肝硬化到 HCC 的疾病进展具有广泛的影响。
